The present invention relates to therapeutic agents for diseases involving Corticotropin Releasing Factor (CRF), such as depression, anxiety, Alzheimer""s disease, Parkinson""s disease, Huntington""s chorea, eating disorders, hypertension, digestive tract diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune system-related diseases.
CRF is a hormone comprising 41 amino acids (Science, 213, 1394-1397, 1981; and J. Neurosci., 7, 88-100, 1987) and it is suggested that CRF plays central roles in bioreactions in stress (Cell. Mol. Neurobiol., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and Neuroendocrinol. 61, 445-452, 1995). CRF acts in two pathways: one acting on the peripheral immune system and sympathetic nervous system via the hypothalamus-pituitary-adrenal system, and another in which it acts as a neurotransmitter in the central nervous system (in Corticotropin Releasing Factor: Basic and Clinical Studies of a Neuropeptide, pp 29-52, 1990). In the case where CRF is intraventricularly administered to hypophysectomized rats and to normal rats, symptoms of anxiety occur in both rats (Pharmacol. Rev., 43, 425-473, 1991; and Brain Res. Rev., 15, 71-100, 1990). Therefore, it is believed that CRF is involved in the hypothalamus-pituitary-adrenal system and that CRF functions as a neurotransmitter in the central nervous system.
The diseases in which CRF is involved are summarized in a review by Owens and Nemeroff in 1991 (Pharmacol. Rev., 43, 425-474, 1991). Namely, CRF is involved in depression, anxiety, Alzheimer""s disease, Parkinson""s disease, Huntington""s chorea, eating disorder, hypertension, digestive tract diseases, drug dependence, inflammation, immune system-related diseases, and the like. Recently, it is reported that CRF is also involved in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, and head trauma (Brain Res. 545, 339-342, 1991; Ann. Neurol. 31, 48-498, 1992; Dev. Brain Res. 91, 245-251, 1996; and Brain Res. 744, 166-170, 1997), and for this reason, CRF-receptor antagonists are useful as therapeutic agents for these diseases.
An objective of the present invention is to provide CRF antagonists effective on therapeutic agents or prophylactic agents for the diseases, which CRF participates in, such as depression, anxiety, Alzheimer""s disease, Parkinson""s disease, Huntington""s chorea, eating disorder, hypertension, digestive apparatus disease, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune system-related diseases.
As a result of diligent research with regard to carbamoyl tetrahydropyridine derivatives, the present inventors discovered novel carbamoyl tetrahydropyridine derivatives which exhibit high affinity for CRF receptors, and in addition, pyrrolopyrimidine derivatives, pyrrole derivatives, and carbamoyl-1,2,3,6-tetrahydropyridines which are intermediates necessary for synthesizing said novel carbamoyl tetrahydropyridine derivatives, consequently completed the present invention.
In the following, the present invention is explained.
The present invention corresponds to a carbamoyl tetrahydropyridine derivative represented by Formula [1] as follows: 
[in the formula, R1 and R2 are identical or different, and each represents a hydrogen atom, a C1-C5 alkyl group, or a phenyl group, or alternatively, R1 and R2, taken together with the nitrogen atom to which they are adjacent, represent a 5- to 8-membered and saturated heterocyclic group represented by the formula: 
(in the formula, A represents CH2, NH, Nxe2x80x94(C1-C5 alkyl), O or S); R3 represents a hydrogen atom or a C1-C5 alkyl group; Y1-Y2 represents (R4)Cxe2x95x90C(R5), (R6)Cxe2x95x90N, Nxe2x95x90N, (R7)Nxe2x80x94CO, or Nxe2x95x90C(R8); X1, X2, and X3 are identical or different, and each represents a hydrogen atom, a halogen atom, a C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkylthio group, a tuifluoromethyl group, a trifluoromethoxy group, an amino group, or a C1-C5 alkylamino group; wherein R4 and R5 are identical or different, and each represents a hydrogen atom or a C1-C5 alkyl group; R6 represents a hydrogen atom or a C1-C5 alkyl group; R7 represents a hydrogen atom, a C1-C5 alkyl group, a (C1-C5 alkoxy)carbonylmethyl group, a carboxymethyl group, or a group represented by the formula: CH2CONR11(R12) (in the formula, R11 and R12 are identical or different, and each represents a hydrogen atom or a C1-C5 alkyl group, or alternatively, R11 and R12, taken together with the nitrogen atom to which they are adjacent, represent a 5- to 8-membered and saturated heterocyclic group represented by the formula: 
(in the formula, B represents CH2, NH, Nxe2x80x94(C1-C5 alkyl), O or S); and R8 represents a hydrogen atom or a carbamoyl group], or a pharmaceutically acceptable salt thereof. Among these, the compounds wherein R1 and R2 represent a hydrogen atom are preferable, and the compounds wherein R3 represents a methyl group; Y1-Y2 represents (R4)Cxe2x95x90C(R5); and R4 and R5 are identical or different, and each represents a hydrogen atom or a methyl group are more preferable.
In addition, another present invention corresponds to a pyrrolopyrimidine derivative represented by Formula [2] as follows: 
(in the formula R3 represents a hydrogen atom or a C1-C5 alkyl group; R4 and R5 are identical or different, and each represents a hydrogen atom or a C1-C5 alkyl group; X4 represents a hydroxyl group, a chlorine atom, a bromine atom, or an iodine atom; and X5 represents a halogen atom, a C1-C5alkyl group, a C1-C5 alkoxy group, a C1-C5 alkylthio group, a trifluoromethyl group, or a trifluoromethoxy group).
Furthermore, another present invention corresponds to a pyrrole derivative represented by Formula [3] as follows: 
(in the formula, R4 and R5 are identical or different, and each represents a hydrogen atom or a C1-C5 alkyl group; and X5 represents a halogen atom, a C1-C5 alkyl group, a C1-C5 alkoxy group, a C1-C5 alkylthio group, a trifluoromethyl group, or a trifluoromethoxy group).
In addition, another present invention corresponds to a 4- or 5-carbamoyl-1,2,3,6-tetrahydropyridine represented by Formula [4] as follows: 
or a pharmaceutically acceptable salt thereof.
In Formula [1] of the present invention, the substituent position of the (R2)R1NCO group is present at the 4-position or the 5-position.
In addition, the terms used in the present invention are defined as follows.
The C1-C5 alkyl group means a straight-chain or branched-chain alkyl group having 1 to 5 carbon atoms. As an example thereof, mention may be made of a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a cyclopropylmethyl group, a pentyl group, an isopentyl group, or the like.
The saturated heterocyclic group means a 5- to 8-membered and saturated heterocyclic group which may include a nitrogen atom, an oxygen atom, or a sulfur atom as an atom for forming the ring, while it is not particularly restricted since any saturated heterocyclic groups capable of providing the compounds represented by Formula (10) shown in the reaction scheme described below may be synthesized. Examples thereof include a pyrrolidino group, a piperidino group, a morpholino group, a thiomorpholino group, a piperazino group, a 4-methylpiperazino group, and the like.
The halogen atom denotes a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The C1-C5 alkoxy group means a straight-chain or branched-chain alkoxy group having 1 to 5 carbon atoms. As an example thereof, mention may be made of a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentyloxy group, an isopentyloxy group, or the like.
The C1-C5 alkylthio group means a straight-chain or branched-chain alkylthio group having 1 to 5 carbon atoms. As an example thereof, mention may be made of a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, a pentylthio group, an isopentylthio group, or the like.
The C1-C5 alkylamino group means an amino group which is substituted with one or two straight-chain or branched-chain alkyl groups having 1 to 5 carbon atoms. As an example thereof, mention may be made of a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, a dipropylamino group, an isopropylamino group, or the like.
The (C1-C5 alkoxy)carbonylmethyl group means a carbonylmethyl group which is substituted with a straight-chain or branched-chain alkoxy group having 1 to 5 carbon atoms. As an example thereof, mention may be made of a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, an is iopropoxycarbonylmethyl group, a butoxycarbonylmethyl group, an isobutoxycarbonylmethyl group, a pentyloxycarbonylmethyl group, an isopentyloxycarbonylmethyl group, or the like.
As an example of the groups represented by the formula: CH2CONR11(R12), mention may be made of, for example, a carbamoylmethyl group, an N-methylcarbamoylmethyl group, an N,N-dimethylcarbamoylmethyl group, an N-ethylcarbamoylmethyl group, an N,N-diethylcarbamoylmethyl group, an N-propylcarbamoylmethyl group, an N,N-dipropylcarbamoylmethyl group, an N-isopropylcarbamoylmethyl group, a pyrrolidinocarbonylmethyl group, a piperidinocarbonylmethyl group, a morpholinocarbonylmethyl group, a piperazinocarbonylmethyl group, or the like.
In addition, the pharmaceutically acceptable salt in the present invention refers to, for example, a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, or phosphoric acid; a salt with an organic acid such as acetic acid, oxalic acid, lactic acid, tartearic acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, or methanesulfonic acid; or the like.
The compounds represented by Formulae [1], [2], [3], and [4] may be prepared as follows:
(in the following reaction schemes, R1, R2, R3, R4, R5, R6, R7, R8, Y1-Y2, X1, X2, X3, X4, and X5 have the same meanings as described above; R9 and R10 are identical or different, each represents a C1-C5 alkyl group or a benzyl group; R13 represents a C1-C5 alkyl group; Boc represents a tert-butoxycarbonyl group; and X6 represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a benzensulfonyloxy group, a toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group). 
A carbamoyltetrahydropyridine derivative (3) which corresponds to the compound of the present invention can be prepared by reacting a 4- or 5-carbamoyl-1,2,3,6-tetrahydropyridine derivative (1) with a compound (2) in the presence or absence of a base, in an inert solvent.
Herein, as examples of the base, mention may be made of, for example, organic bases such as triethylamine, diisopropylethylamine, or pyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, or sodium hydride; alcoholates such as sodium methoxide, sodium ethoxide, or potassium tert-butoxide; metal amides such as sodium amide, or lithium diisopropylamide; or Grignard reagents such as methyl magnesium bromide; or the like. As examples of the inert solvent, mention may be made of, for example, alcohols such as methanol, ethanol, isopropyl alcohol, or ethylene glycol; ethers such as diethyl ether, tetrahydrofuran, dioxane, or 1,2-dimethoxyethane; hydrocarbons such as benzene or toluene; amides such as N,N-dimethylformamide; acetonitrile; water; mixed solvents selected from these solvents; or the like. 
A 4-carbamoyl-1,2,3,6-tetrahydropyridine derivative (4) can be prepared by a sequence of operations of N-protection on a 1,2,3,6-tetrahydropyridine-4-carboxylic acid (7), amidation, and deprotection of N-Boc. The 1,2,3,6-tetrahydropyridine-4-carboxylic acid (7) may be synthesized by conversion of the methyl group of a N-methyl-4-alkoxycarbonyl-1,2,3,6-tetrahydropyridine (5), followed by a hydrolysis.
Herein, the conversion of the methyl group means to replace the N-methyl group with an alkoxycarbonyl group, and for example, to react with haloformates such as ethyl chloroformate or benzyl chloroformate in the presence or absence of an organic base such as diisopropylethylamine or an inorganic base such as potassium carbonate in an inert solvent such as benzene, toluene, chloroform, or the like. The hydrolysis means elimination of an N-substituent of a compound (6) and hydrolysis of an ester group, and for example, means to react under an acidic condition such as with hydrobromic acid or a basic condition such as with barium hydroxide. The N-protection means to protect the NH group of the compound (7) with a tert-butoxycarbonyl group (Boc), and for example, N-Boc protection can be conducted by the common methods using (Boc)2O or the like. The amidation refers to, for example, an amidation via an acid halide such as an acid chloride or an acid bromide, an amidation via an anhydride of a mixed acid using haloformates such as ethyl chloroformate, isobutyl chloroformate, or a common amidation: using a condensing agent such as 1-(3,3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,3-dicyclohexylcarbodiimide, diphehylphosphorylazide, diethyl cyanophosphate, or carbonyldiimidazole. Deprotection of N-Boc refers to a general reaction for removing a Boc group, and for example, refers to reacting, for example, trifluoroacetic acid, hydrogen chloride, formic acid, or the like in an inert solvent such as ethyl acetate, dichloromethane, chloroform, dioxane, water or the like. With regard to the hydrolysis of the ester, N-protection, and deprotection of N-Boc, the methods as described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, written by THEODORA W. GREENE and PETER G. M. WUTS may be employed. 
A 5-carbamoyl-1,2,3,6-tetrahydropyridine derivative (12) can be prepared from an N-Boc-1,2,3,6-tetrahydropyridine-5-carboxylic acid (18), in the same manner as that of the synthesis method of said 4-carbamoyl-1,2,3,6-tetrahydropyridine derivative (4) from said N-Boc-1,2,3,6-tetrahydropyridine-4-carboxylic acid (9). The N-Boc-1,2,3,6-tetrahydropyridine-5-carboxylic acid (18) can be derived by a condensation reaction of an N-Boc-4-piperidone (13) with a dialkyl carbonate, reduction, and elimination of the hydroxyl group, followed by a hydrolysis.
Herein, the condensation with a dialkyl carbonate refers to reacting with the dialkyl carbonates such as dimethyl carbonate or diethyl carbonate in the presence of a base, examples of which include, for example, inorganic bases such as sodium hydride or potassium hydride; alcoholates such as sodium methoxide, sodium ethoxide, or potassium tert-butoxide; metal amides such as sodium amide or lithium diisopropylamide; or the like, in an inert solvent, examples of which include, for example, alcohols such as methanol, ethanol, isopropyl alcohol, or ethylene glycol; ethers such as diethyl ether, tetrahydrofuran, dioxane, or 1,2-dimethoxyethane; hydrocarbons such as benzene or toluene; amides such as N,N-dimethylformamide; or the like. The reduction refers to a reduction of common ketones to alcohols, and for example, refers to a reduction by inorganic reductants such as sodium borohydride; a reduction by hydrogenation using palladium/carbon, platinum oxide, or the like; or the like. The elimination of the hydroxyl group refers to converting the hydroxyl group of the compound (16) into a leaving group followed by a reaction, and refers to, for example, a halogenation by thionyl chloride, triphenylphosphine-carbon tetrabromide, or the like; an acylation, for example, by acetyl chloride, or the like; or a sulfonylation, for example, by methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride, followed by an elimination reaction by a base treatment with, for example 1,8-diazabicyclo[5.4.0]-7-undecene, pyridine, or the like. The hydrolysis refers to a common hydrolysis of esters, and for example, refers to reacting using a base such as sodium hydroxide or potassium hydroxide in an inert solvent such as alcohol, water, or the like. With regard to the hydrolysis of the ester, the methods as described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, written by THEODORA W. GREENE and PETER G. M. WUTS may be employed. 
A pyrrole derivative (23), which is a compound of the present invention, can be prepared by reacting an aniline derivative (19) and a compound (20) in the presence of organic acids, inorganic acids, or Lewis acids, such as p-toluene sulfonic acid, hydrogen chloride, zinc chloride, or the like, under azeotropic dehydration conditions in a solvent of hydrocarbons such as toluene, adding malononitrile (21) to this reaction mixture, and reacting the mixture, under azeotropic dehydration conditions, or while the solvent is being removed by heating to 150 to 250xc2x0 C. Alternatively, the pyrrole derivative (23) can also be prepared by reacting the aniline derivative (19) and an ethylidene malononitrile derivative (22) in the presence or absence of a base in the presence or absence of an inert solvent at a reaction temperature ranging from room temperature to 250xc2x0 C. Herein, as examples of the inert solvent, mention may be made of, for example, alcohols such as ethanol or isopropyl alcohol; hydrocarbons such as toluene or benzene; ethers such as tetrahydrofuran or 1,2-dimethoxyethane; or the like. Examples of the base include, for example, inorganic bases such as sodium hydride or potassium carbonate or organic bases such as pyridine, N-methylmorpholine, or triethylamine.
In addition, the pyrrole derivative (23) is reacted with an acid anhydride such as acetic anhydride in an inert solvent such as acetic acid at a temperature ranging from an ice-cooled temperature to 150xc2x0 C., and subsequently, a treatment is carried out using inorganic acids such as phosphoric acid at a temperature ranging from an ice-cooled temperature to 150xc2x0 C., thereby a pyrrolopyrimidine derivative (24) which is the compound of the present invention can be obtained.
In addition, the pyrrolopyrimidine derivative (24) is reacted with a halogenating agent such as phosphorus oxychloride at a temperature ranging from room temperature to 150xc2x0 C., thereby a derivative (25) which is the compound of the present invention can be derived.
The compounds of the present invention are useful as therapeutic agents or prophylactic agents for diseases which are considered to involve CRF. For this purpose, the compounds of the present invention may be formulated into tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, injections, or the like, according to the conventional formulation methods, by adding fillers, binders, disintegrants, pH regulators, solubilizers, and the like, which are in common use.
The compounds of the present invention may be administered orally or parenterally to an adult patient in a quantity of 0.1 to 500 mg per day in a single dose or divided doses. The dose can be increased or decreased as appropriate in consideration of the type of disease being treated, and the age, weight, and symptoms of each individual patient.